Somatostatin (SS) is one of several peptides cleaved during the post translational processing of pro-SS. SS and SS-related peptides (SRP) are released by cells in brain, hypothalamus, pancreas and intestine and at least two SRP are known to suppress the secretion of several peptides involved in fuel homeostasis. The overall aim of this proposal is to evaluate the hypothesis that SS28, a product of processing of pro-SS, is preferentially released from the small intestine and, transported to the endocrine pancreas in the circulation, acts as a physiological modulator of postprandial insulin secretion. Four specific questions include: 1) is the small intestine the principal source of circulating SRP?; 2) if so, what are the signals that lead to their secretion?; 3) does SS28 and other precursors exert effects both locally and on distant cells?; and 4) is the secretion of SRP perturbed in and contribute to hormonal changes in pathologic states? These questions will be tested in man, baboon and rat. Measurements of SRP will be made by radioimmunoassay using antisera specific for different regions of pro-SS. These include SS28, SS28(1-12), SS28(1-14), and SS28(15-28), as well as two precursors of SS28 of estimated MW of 12 and 5 K daltons. SRP in the peripheral circulation of normal man will be evaluated in response to oral and IV nutriments, substrates, neurotransmitters, and peptides. The content of SRP and their biosynthetic pathways will be examined in human intestinal mucosa obtained by biopsy. Possible alterations in secretion of SRP in man with metabolic and intestinal disorders will be evaluated. Hepatic clearance of SRP will be examined in the baboon. The release of SRP into the venous and luminal effluent in the in situ perfused rat small intestine will be evaluated to determine if different peptides are secreted. To test the hypothesis that circulating SS28 and possibly other SRP influence insulin secretion, passive neutralization experiments with antisera against SRP, and depletion of tissue levels of SRP with cysteamine will be carried out. The long-term objective is to determine if SRP release during nutriment absorption act to restrain postprandial events in fuel homeostasis.